Original Paper
Ophthalmologica
Ophthalmologica 2014;232:207–215 DOI: 10.1159/000364956
Received: April 16, 2014 Accepted: May 28, 2014 Published online: November 28, 2014
Intravitreal Dexamethasone Implant for Macular Edema Secondary to Retinal Vein Occlusion: 12-month Follow-Up and Prognostic Factors Emilia Maggio a Antonio Polito a Massimo Guerriero b Grazia Pertile a a
Sacrocuore Hospital, Negrar, and b Department of Computer Science, University of Verona, Verona, Italy
Key Words Macular edema · Retinal vein occlusion · Dexamethasone · Prognostic factors
Abstract Purpose: To evaluate anatomical and visual outcomes following intravitreal dexamethasone implantation (Ozurdex) in eyes with visual loss due to macular edema (ME) secondary to retinal vein occlusion (RVO) and to identify predictive factors for improvement in best-corrected visual acuity (BCVA). Methods: We retrospectively analyzed medical records of 43 consecutive eyes with treatment-naïve ME secondary to recent onset RVO treated with repeated Ozurdex injections on a pro re nata basis. Results: The mean follow-up (FU) duration was 14 months (min. 12, max. 22). Both mean BCVA and central macular thickness improved significantly at the end of the FU period (p = 0.0001), and more than 30% of the eyes gained ≥3 lines within 3 months of repeated injections. Presence of foveal serous retinal detachment and macular ischemia were negatively associated with visual outcomes. Improvements were significantly associated with baseline BCVA and the integrity of the ellipsoid zone. No serious adverse events were recorded. Conclusions: In our study population, Ozurdex was a safe and effective therapeutic option for the treatment of ME associated with RVO. The results suggest that a comprehensive approach in the examination of RVO eyes may help to predict which patients are most likely to benefit from the treatment. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0030–3755/14/2324–0207$39.50/0 E-Mail [email protected] www.karger.com/oph
Introduction
Retinal vein occlusion (RVO) is the second most common cause of vision loss due to retinal vascular disease [1]. Macular edema (ME) is a common complication of both ischemic and nonischemic RVO [2, 3]. The pathogenesis of ME in RVO is multifactorial and still not entirely understood. Inflammatory cytokines have been found to play an important role in its development. Several studies have found eyes with RVO to have elevated levels of interleukin-6, prostaglandins and VEGF [4–7]. Increase in inflammatory cytokines leads to vasodilation, increased vascular permeability and a breakdown of the inner blood-retina barrier by a dysregulation of the endothelial tight-junction proteins. Corticosteroids have potent anti-inflammatory properties and have been seen to inhibit many cytokines involved in the development of ME in RVO including VEGF, interleukin-6, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. The phase III GENEVA clinical trial, conducted on 1,267 patients, randomized dexamethasone intravitreal implantation (Ozurdex) against a sham treatment and found Ozurdex to be safe and effective in improving visual acuity and reducing the risk of vision loss [8, 9]. Further ‘real-life’ studies describing series of patients treated with Ozurdex for ME due to RVO in multicentric or single-center institutional settings have found clinically meaningful benefits and no serious adverse events [10– Emilia Maggio Via Don Sempreboni, 5 IT–37024 Negrar, Verona (Italy) E-Mail emi_maggio @ yahoo.it
18]. However, 12-month clinical data have rarely been reported in the previous literature nor has analysis on treatment-naïve eyes with recent onset disease. Moreover, there is still scarce knowledge concerning predictive factors for visual outcomes. Also to consider is the management of ME in eyes affected by ischemic RVO and with low baseline visual acuity. In fact, these eyes are often excluded from clinical trials [8, 19, 20]; therefore evidence for the efficacy of any treatment in these eyes is mostly lacking. The purpose of the present study was to evaluate, in our routine clinical practice, the anatomical and visual outcomes following repeated Ozurdex injections in eyes with treatment-naïve ME secondary to recent onset RVO, both ischemic and nonischemic, followed up for at least 12 months; we also investigated various potential predictive factors for improvement in visual acuity, including baseline best-corrected visual acuity (BCVA), central macular thickness (CMT), macular perfusion status, presence of foveal serous retinal detachment (SRD) and the integrity of the ellipsoid zone (EZ).
Methods The study included eyes of consecutive patients receiving intravitreal Ozurdex injections as treatment for ME secondary to branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO) or hemicentral retinal vein occlusion (HRVO). Medical records were reviewed retrospectively. Patients received the first injection between June 2011 and August 2012. Retreatment with Ozurdex was performed on a pro re nata basis. Criterion for retreatment was a recurrence of ME on optical coherence tomography (OCT) scanning associated with a loss of BCVA of at least 1 line. Exclusion criteria were the presence of concomitant diseases that could affect BCVA, such as choroidal neovascularization, diabetic retinopathy, a history of ocular inflammation, epiretinal membrane and vitreomacular traction. We also excluded eyes with a history of vitreoretinal surgery or with any ocular surgery performed in the previous 8 months, as well as eyes with high myopia (>4 dpt) and severe media opacities. The study population included only eyes affected by newly diagnosed previously untreated ME associated with recent onset RVO – a minimum follow-up (FU) of 12 months and at least a 3-month interim after the latest Ozurdex injection. Eyes were excluded from the study in case of disease duration >10 weeks. Informed consent was obtained from the patients in accordance with the Declaration of Helsinki. At baseline all eyes underwent a complete ophthalmological examination, including BCVA, slitlamp biomicroscopy, intraocular pressure (IOP) evaluation, dilated fundus examination with a 90-dpt indirect lens, OCT and fluorescein angiography with the Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany). BCVA was measured by Snellen visual charts and converted to logarithm of the minimum angle of resolution (logMAR) units for statistical analysis.
208
Ophthalmologica 2014;232:207–215 DOI: 10.1159/000364956
RVO was classified into nonischemic and ischemic at the initial visit; conversion of nonischemic to ischemic was carefully evaluated during the FU. Criteria to differentiate ischemic from nonischemic RVO are under debate [21]. Nevertheless, in this study, the primary criterion for this differentiation was the presence of at least 10 disk areas of retinal capillary obliteration, in accordance with the Central Vein Occlusion Study [22] and with many other previous studies. In addition, functional tests, such as relative afferent pupillary defect, baseline visual acuity and, when available, visual field, were also taken into account. All eyes affected by ischemic RVO with evidence of neovascularization or those at high risk of its development underwent laser photocoagulation of areas of peripheral retinal nonperfusion. During the FU, the physician also evaluated whether to add other medical and/or laser treatments in case of incomplete response to the Ozurdex injection. In the evaluation of treatment efficacy, the primary outcome measures were improvements of BCVA and CMT from baseline over the entire FU period. Secondary end points were the number of eyes gaining ≥3 lines from baseline within 3 months of each injection. Subgroup analyses for BRVO and CRVO/HRVO eyes were performed in order to evaluate differences between these two entities. Moreover, additional subgroup analyses were performed for eyes affected by ischemic and nonischemic RVO and for eyes with baseline VA ≥1 logMAR. The following potential prognostic factors were studied: patient age and gender, additional treatments applied, baseline BCVA, perfusion status of the macula, CMT, presence of SRD at baseline and integrity of the EZ at the final visit. SRD was assumed to be present if the posterior surface of the retina was elevated above the retinal pigment epithelium. The detectability of EZ morphology at baseline was difficult in cases where hemorrhages and exudates obscured the outer retinal layers. Therefore this parameter was not included in the evaluation of prognostic factors. Evaluation of EZ integrity at the final visit was possible, however, in all the eyes. In particular, it was evaluated in the central 1,000 μm centered on the fovea. The status of the EZ was defined as follows: (1) EZ integrity detected in the foveal area; (2) EZ detected as a disrupted line beneath the fovea; (3) EZ loss in the fovea. Fluorescein angiography at baseline was analyzed to assess the perfusion status of the macula. In case of hemorrhages obscuring the perfusion of the macular area, it was re-evaluated at the resorption of hemorrhages. Presence of macular ischemia was defined in case of broken perifoveal capillary rings at the borders of the foveal avascular zone with distinct areas of capillary nonperfusion within one disk diameter of the foveal center. Evaluation of OCT and fluorescein angiography images was performed by 2 trained examiners masked to BCVA. Ninety-eight percent of the first examiner’s findings were consistent with those of the second. Intergrader reliability (k) was assessed with a k value –0.96 (p < 0.0001). Implant safety was assessed at each FU visit. The presence of lens opacities was evaluated during slitlamp examination. An IOP increase was determined when IOP ≥5 mm Hg compared to baseline. Data concerning the previous use of IOP medication, IOP changes, need of additional IOP-lowering medications, cataract or glaucoma surgeries and other adverse events were collected. Statistical analyses were performed using STATA (StataCorp, College Station, Tex., USA) version 12.0.
Maggio/Polito/Guerriero/Pertile
Table 1. Baseline characteristics of the study population
Study population Number of eyes Gender (male/female), n Age, years Mean ± SD Min.–max. Pseudophakic eyes, n Mean baseline VA ± SD, logMAR Mean baseline CMT ± SD, μm Eyes with baseline VA ≥1 logMAR, n Ischemic RVO, n
Results are expressed as mean and standard deviation if variables are continuous, and as a percentage if variables are categorical. The Shapiro-Wilk test was used to test the normality for a continuous variable. The paired t test was used to compare the mean of a continuous variable before and after observation. A multiple stepwise regression model was used to choose the best subset predictor variables of BCVA. A significance level equal to 0.2 was used for removal of the variables from the model. A p value
Ophthalmologica
Ophthalmologica 2014;232:207–215 DOI: 10.1159/000364956
Received: April 16, 2014 Accepted: May 28, 2014 Published online: November 28, 2014
Intravitreal Dexamethasone Implant for Macular Edema Secondary to Retinal Vein Occlusion: 12-month Follow-Up and Prognostic Factors Emilia Maggio a Antonio Polito a Massimo Guerriero b Grazia Pertile a a
Sacrocuore Hospital, Negrar, and b Department of Computer Science, University of Verona, Verona, Italy
Key Words Macular edema · Retinal vein occlusion · Dexamethasone · Prognostic factors
Abstract Purpose: To evaluate anatomical and visual outcomes following intravitreal dexamethasone implantation (Ozurdex) in eyes with visual loss due to macular edema (ME) secondary to retinal vein occlusion (RVO) and to identify predictive factors for improvement in best-corrected visual acuity (BCVA). Methods: We retrospectively analyzed medical records of 43 consecutive eyes with treatment-naïve ME secondary to recent onset RVO treated with repeated Ozurdex injections on a pro re nata basis. Results: The mean follow-up (FU) duration was 14 months (min. 12, max. 22). Both mean BCVA and central macular thickness improved significantly at the end of the FU period (p = 0.0001), and more than 30% of the eyes gained ≥3 lines within 3 months of repeated injections. Presence of foveal serous retinal detachment and macular ischemia were negatively associated with visual outcomes. Improvements were significantly associated with baseline BCVA and the integrity of the ellipsoid zone. No serious adverse events were recorded. Conclusions: In our study population, Ozurdex was a safe and effective therapeutic option for the treatment of ME associated with RVO. The results suggest that a comprehensive approach in the examination of RVO eyes may help to predict which patients are most likely to benefit from the treatment. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0030–3755/14/2324–0207$39.50/0 E-Mail [email protected] www.karger.com/oph
Introduction
Retinal vein occlusion (RVO) is the second most common cause of vision loss due to retinal vascular disease [1]. Macular edema (ME) is a common complication of both ischemic and nonischemic RVO [2, 3]. The pathogenesis of ME in RVO is multifactorial and still not entirely understood. Inflammatory cytokines have been found to play an important role in its development. Several studies have found eyes with RVO to have elevated levels of interleukin-6, prostaglandins and VEGF [4–7]. Increase in inflammatory cytokines leads to vasodilation, increased vascular permeability and a breakdown of the inner blood-retina barrier by a dysregulation of the endothelial tight-junction proteins. Corticosteroids have potent anti-inflammatory properties and have been seen to inhibit many cytokines involved in the development of ME in RVO including VEGF, interleukin-6, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. The phase III GENEVA clinical trial, conducted on 1,267 patients, randomized dexamethasone intravitreal implantation (Ozurdex) against a sham treatment and found Ozurdex to be safe and effective in improving visual acuity and reducing the risk of vision loss [8, 9]. Further ‘real-life’ studies describing series of patients treated with Ozurdex for ME due to RVO in multicentric or single-center institutional settings have found clinically meaningful benefits and no serious adverse events [10– Emilia Maggio Via Don Sempreboni, 5 IT–37024 Negrar, Verona (Italy) E-Mail emi_maggio @ yahoo.it
18]. However, 12-month clinical data have rarely been reported in the previous literature nor has analysis on treatment-naïve eyes with recent onset disease. Moreover, there is still scarce knowledge concerning predictive factors for visual outcomes. Also to consider is the management of ME in eyes affected by ischemic RVO and with low baseline visual acuity. In fact, these eyes are often excluded from clinical trials [8, 19, 20]; therefore evidence for the efficacy of any treatment in these eyes is mostly lacking. The purpose of the present study was to evaluate, in our routine clinical practice, the anatomical and visual outcomes following repeated Ozurdex injections in eyes with treatment-naïve ME secondary to recent onset RVO, both ischemic and nonischemic, followed up for at least 12 months; we also investigated various potential predictive factors for improvement in visual acuity, including baseline best-corrected visual acuity (BCVA), central macular thickness (CMT), macular perfusion status, presence of foveal serous retinal detachment (SRD) and the integrity of the ellipsoid zone (EZ).
Methods The study included eyes of consecutive patients receiving intravitreal Ozurdex injections as treatment for ME secondary to branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO) or hemicentral retinal vein occlusion (HRVO). Medical records were reviewed retrospectively. Patients received the first injection between June 2011 and August 2012. Retreatment with Ozurdex was performed on a pro re nata basis. Criterion for retreatment was a recurrence of ME on optical coherence tomography (OCT) scanning associated with a loss of BCVA of at least 1 line. Exclusion criteria were the presence of concomitant diseases that could affect BCVA, such as choroidal neovascularization, diabetic retinopathy, a history of ocular inflammation, epiretinal membrane and vitreomacular traction. We also excluded eyes with a history of vitreoretinal surgery or with any ocular surgery performed in the previous 8 months, as well as eyes with high myopia (>4 dpt) and severe media opacities. The study population included only eyes affected by newly diagnosed previously untreated ME associated with recent onset RVO – a minimum follow-up (FU) of 12 months and at least a 3-month interim after the latest Ozurdex injection. Eyes were excluded from the study in case of disease duration >10 weeks. Informed consent was obtained from the patients in accordance with the Declaration of Helsinki. At baseline all eyes underwent a complete ophthalmological examination, including BCVA, slitlamp biomicroscopy, intraocular pressure (IOP) evaluation, dilated fundus examination with a 90-dpt indirect lens, OCT and fluorescein angiography with the Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany). BCVA was measured by Snellen visual charts and converted to logarithm of the minimum angle of resolution (logMAR) units for statistical analysis.
208
Ophthalmologica 2014;232:207–215 DOI: 10.1159/000364956
RVO was classified into nonischemic and ischemic at the initial visit; conversion of nonischemic to ischemic was carefully evaluated during the FU. Criteria to differentiate ischemic from nonischemic RVO are under debate [21]. Nevertheless, in this study, the primary criterion for this differentiation was the presence of at least 10 disk areas of retinal capillary obliteration, in accordance with the Central Vein Occlusion Study [22] and with many other previous studies. In addition, functional tests, such as relative afferent pupillary defect, baseline visual acuity and, when available, visual field, were also taken into account. All eyes affected by ischemic RVO with evidence of neovascularization or those at high risk of its development underwent laser photocoagulation of areas of peripheral retinal nonperfusion. During the FU, the physician also evaluated whether to add other medical and/or laser treatments in case of incomplete response to the Ozurdex injection. In the evaluation of treatment efficacy, the primary outcome measures were improvements of BCVA and CMT from baseline over the entire FU period. Secondary end points were the number of eyes gaining ≥3 lines from baseline within 3 months of each injection. Subgroup analyses for BRVO and CRVO/HRVO eyes were performed in order to evaluate differences between these two entities. Moreover, additional subgroup analyses were performed for eyes affected by ischemic and nonischemic RVO and for eyes with baseline VA ≥1 logMAR. The following potential prognostic factors were studied: patient age and gender, additional treatments applied, baseline BCVA, perfusion status of the macula, CMT, presence of SRD at baseline and integrity of the EZ at the final visit. SRD was assumed to be present if the posterior surface of the retina was elevated above the retinal pigment epithelium. The detectability of EZ morphology at baseline was difficult in cases where hemorrhages and exudates obscured the outer retinal layers. Therefore this parameter was not included in the evaluation of prognostic factors. Evaluation of EZ integrity at the final visit was possible, however, in all the eyes. In particular, it was evaluated in the central 1,000 μm centered on the fovea. The status of the EZ was defined as follows: (1) EZ integrity detected in the foveal area; (2) EZ detected as a disrupted line beneath the fovea; (3) EZ loss in the fovea. Fluorescein angiography at baseline was analyzed to assess the perfusion status of the macula. In case of hemorrhages obscuring the perfusion of the macular area, it was re-evaluated at the resorption of hemorrhages. Presence of macular ischemia was defined in case of broken perifoveal capillary rings at the borders of the foveal avascular zone with distinct areas of capillary nonperfusion within one disk diameter of the foveal center. Evaluation of OCT and fluorescein angiography images was performed by 2 trained examiners masked to BCVA. Ninety-eight percent of the first examiner’s findings were consistent with those of the second. Intergrader reliability (k) was assessed with a k value –0.96 (p < 0.0001). Implant safety was assessed at each FU visit. The presence of lens opacities was evaluated during slitlamp examination. An IOP increase was determined when IOP ≥5 mm Hg compared to baseline. Data concerning the previous use of IOP medication, IOP changes, need of additional IOP-lowering medications, cataract or glaucoma surgeries and other adverse events were collected. Statistical analyses were performed using STATA (StataCorp, College Station, Tex., USA) version 12.0.
Maggio/Polito/Guerriero/Pertile
Table 1. Baseline characteristics of the study population
Study population Number of eyes Gender (male/female), n Age, years Mean ± SD Min.–max. Pseudophakic eyes, n Mean baseline VA ± SD, logMAR Mean baseline CMT ± SD, μm Eyes with baseline VA ≥1 logMAR, n Ischemic RVO, n
Results are expressed as mean and standard deviation if variables are continuous, and as a percentage if variables are categorical. The Shapiro-Wilk test was used to test the normality for a continuous variable. The paired t test was used to compare the mean of a continuous variable before and after observation. A multiple stepwise regression model was used to choose the best subset predictor variables of BCVA. A significance level equal to 0.2 was used for removal of the variables from the model. A p value
